IL-17-driven mechanisms for tumor progression and resistance to therapies

IL-17 驱动的肿瘤进展和治疗耐药机制

• 批准号: 10493940
• 负责人: Xiaoxia Li
• 金额: $ 52.03万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493940
• 关键词: Animal Model; Automobile Driving; Award; Binding; CD8-Positive T-Lymphocytes; Cells; Chemoresistance; Chronic; Cisplatin; Collagen; Cutaneous; Data; Deposition; Development; Dissection; Environment; Epidermal Growth Factor Receptor; Exclusion; Fibroblasts; Genes; Genetic; Goals; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immune checkpoint inhibitor; Immunotherapy; Infiltration; Inflammation; Inflammatory; Interleukin-17; Interleukins; Knowledge; Link; MAPK7 gene; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Mus; Myeloid-derived suppressor cells; Pathogenicity; Population; Process; Prognosis; Proteins; RNA Binding; Refractory; Reporting; Resistance; Role; Shapes; Signal Transduction; Solid Neoplasm; Squamous cell carcinoma; Standardization; Statistical Data Interpretation; Stromal Cells; Testing; Therapeutic; Transcript; Transforming Growth Factor beta; Translations; Work; antagonist; anti-PD-1; anti-PD1 therapy; base; cancer cell; cancer cell differentiation; cancer therapy; chemotherapy; cytokine; design; improved; in vivo; insight; neoplastic cell; novel therapeutic intervention; pre-clinical assessment; prevent; programs; response; single cell analysis; stem; stem cells; stemness; therapeutic target; therapy resistant; tool; transcriptome; transcriptomics; treatment response; tumor; tumor microenvironment; tumor progression; tumorigenesis; wound healing

Project Summary While the relationship between chronic inflammation and cancer is well recognized, knowledge of the cellular and molecular mechanisms that link these processes continues to evolve. Intratumoral interleukin 17A (IL-17) levels are associated with poor prognosis for a variety of solid tumors in human. The overall goal of this application is to investigate the mechanisms of IL-17-mediated cancer progression, focusing on tumor responses to anti-cancer therapies. Our recent preliminary data revealed that IL-17 engages both cancer cells and tumor microenvironment to synergistically promote cancer progression. Firstly, work supported by this award identified a non-canonical IL-17-induced EGFR-mediated ERK5 signaling cascade critical for tumorigenesis. Our new preliminary study revealed an Lrig1+ stem-like tumor cell population in squamous cell carcinoma that are highly responsive to IL-17 with EGFR-ERK5 activation. Transcriptomic profiling revealed a link between IL-17-ERK5 axis in human and mouse Lrig1+ stem-like tumor cells with NRF2-mediated antioxidation and Wnt5a-dependent induction of stemness. Lineage tracing showed that IL-17 rendered these Lrig1+ stem-like tumor cells resistance to chemotherapy, which were also enriched by anti-PD1 treatment. Secondly, we found that canonical IL-17 signaling operates in both tumor cells and stromal cells to dictate a tumor-promoting and immune suppressive environment. In tumor cells, IL-17 synergizes with other inflammatory cytokines to orchestrate an intratumoral cancer promoting inflammation via the induction of specific effector molecules. In cancer-associated fibroblasts, IL-17 signaling helps to establish an immune exclusion zone to prevent the infiltration of CD8+ T cells. Deletion of IL-17R in CAFs rendered these tumors sensitive to immune therapy. Based on these observations, we hypothesize that canonical and non-canonical IL-17 signaling in cancer cells and CAFs coordinately drive cancer progression and resistance to therapies. To test this hypothesis, we will (1) Investigate how IL-17R-EGFR axis in Lrig1+ stem-like tumor cells renders resistance to anti-cancer therapies; (2) Elucidate the mechanism by which IL-17 shapes the pro-tumor immune exclusive tumor microenvironment. Program Interactions: This Project will be critically informed by and also provide necessary information to the other Projects in the Program at multiple levels. Project 1 and Project 2 will investigate the antagonistic interplay between IFNβ and TGFβ in cancer cell differentiation. Informed by those studies, we will determine whether STING-induced IFNβ can be used to eradicate Lrig1+ cells to improve responses to anti-cancer therapies. We will take advantage of the Animal Model, Immunotyping and Analytics Core B to standardize our in vivo analyses, including preclinical assessment of cancer therapeutics and characterization of the tumor microenvironment (TME). Statistical analyses will be performed by Program Biostatistician Dr. Bo Hu and Program Bioinformatician Dr. Fulai Jin (Core B).

项目摘要 虽然慢性炎症和癌症之间的关系已经得到了很好的认识，但对细胞 而连接这些过程的分子机制仍在继续进化。肿瘤内白介素17A(IL-17) 在人类的多种实体肿瘤中，其水平与预后不良有关。这个项目的总体目标是 应用是研究IL-17介导的肿瘤进展的机制，重点是肿瘤反应 为了抗癌治疗。我们最近的初步数据显示，IL-17与癌细胞和肿瘤都有接触 微环境协同促进癌症进展。首先，由该奖项支持的工作确定 非规范的IL-17诱导的EGFR介导的ERK5信号级联对肿瘤的发生至关重要。我们的新产品 初步研究显示，在鳞状细胞癌中存在Lrig1+干细胞样瘤细胞群，这些细胞群高度 通过EGFR-ERK5激活对IL-17作出反应。转录图谱显示IL-17-ERK5之间存在联系 NRF2介导的抗氧化和Wnt5a依赖的人和小鼠Lrig1+干细胞样瘤细胞中的Axis 茎的诱导。谱系追踪显示IL-17使这些Lrig1+干细胞对肿瘤细胞产生抵抗 化疗，这也通过抗PD1治疗而得到加强。其次，我们发现经典的IL-17 信号在肿瘤细胞和基质细胞中都起作用，从而决定肿瘤的促进和免疫抑制。 环境。在肿瘤细胞中，IL-17与其他炎性细胞因子协同作用，协调肿瘤内 癌症通过诱导特定的效应分子来促进炎症。在癌症相关的成纤维细胞中， IL-17信号有助于建立免疫排斥区，防止CD8+T细胞的渗透。删除 CAF中IL-17R的表达使这些肿瘤对免疫治疗敏感。基于这些观察，我们 肿瘤细胞和CAF中典型和非典型IL-17信号协同致癌假说 进展和对治疗的抵抗。为了验证这一假设，我们将(1)研究IL-17R-EGFR轴是如何 在Lrig1+干细胞样肿瘤细胞对抗癌治疗产生抵抗；(2)阐明 IL-17塑造亲肿瘤免疫排他性肿瘤微环境。计划互动：此项目将 获得本计划中其他项目的重要信息，并向其提供必要的信息 级别。项目1和项目2将研究干扰素β和转化生长因子β在癌细胞中的拮抗作用 差异化。根据这些研究，我们将确定刺痛诱导的干扰素β是否可以用于 清除Lrig1+细胞以提高对抗癌治疗的反应。我们将利用动物的优势 模型、免疫分型和分析核心B，以标准化我们的体内分析，包括临床前分析 癌症治疗的评估和肿瘤微环境(TME)的特征。统计 分析将由计划生物统计学家博虎博士和计划生物信息学家金福来博士进行 (核心B)。